Increased fMRI connectivity upon chemogenetic inhibition of the mouse prefrontal cortex

Abstract

While shaped and constrained by axonal connections, fMRI-based functional connectivity reorganizes in response to varying interareal input or pathological perturbations. However, the causal contribution of regional brain activity to whole-brain fMRI network organization remains unclear. Here we combine neural manipulations, resting-state fMRI and in vivo electrophysiology to probe how inactivation of a cortical node causally affects brain-wide fMRI coupling in the mouse. We find that chronic inhibition of the medial prefrontal cortex (PFC) via overexpression of a potassium channel increases fMRI connectivity between the inhibited area and its direct thalamo-cortical targets. Acute chemogenetic inhibition of the PFC produces analogous patterns of fMRI overconnectivity. Using in vivo electrophysiology, we find that chemogenetic inhibition of the PFC enhances low frequency (0.1–4 Hz) oscillatory power via suppression of neural firing not phase-locked to slow rhythms, resulting in increased slow and δ band coherence between areas that exhibit fMRI overconnectivity. These results provide causal evidence that cortical inactivation can counterintuitively increase fMRI connectivity via enhanced, less-localized slow oscillatory processes.

Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions

“…Since slow oscillations of delta-band fluctuations contribute to functional connectivity (Wang et al, 2012) and are characterized by brain-wide synchrony (Pan et al, 2013; Uhlhaas et al, 2010), we speculate that differences in low-frequency power changes between the neuromodulated CPdm and cortex contribute to our observations of decreased striato-cortical functional connectivity after exciting D1 MSNs. Moreover, recent findings illustrate that low power coherence between chemogenetically inhibited areas and remote non-neuromodulated areas also contributes to shaping functional connectivity between those regions (Rocchi et al, 2022) . This indicates that more comprehensive analysis combining electrophysiology with fMRI could provide clearer insights into the mechanisms behind observed changes in functional connectivity.…”

“…Perturbing an individual component at the cellular level can alter both the local neural dynamics and patterns of inter-regional communication with the rest of the brain. A large body of work has used functional magnetic resonance imaging at rest (rsfMRI) to investigate interregional functional connectivity (FC) at the macroscale with cellular manipulations (Markicevic et al, 2020;Nakamura et al, 2020;Rocchi et al, 2022;Zerbi et al, 2019) and without (Chuang & Nasrallah, 2017;Gozzi & Schwarz, 2016;Grandjean et al, 2020). But relatively few studies have focused on directly capturing the local dynamical properties of BOLD signal fluctuations within brain areas.…”

A model of the mouse cortex with attractor dynamics explains the structure and emergence of rsfMRI co-activation patterns

“…Interestingly, our model predicted that 7 out of 31 stationary attractors (1,7,11,17,23,30,31, plotted in Fig. 3G) were homotopic, and the remaining stationary attractors were non-homotopic, and occurred in pairs with spatially opposed configurations ((2, 6), (3,14), (4,20), (5,25), (8,15), (9,21), (10,26), (12,16), (13,27), (18,22), (19,28), (24,29), plotted in Fig. S3F).…”

“…In recent years, studies of rsfMRI in humans have begun to be complemented by similar measures performed in preclinical species, including rodents. Mouse rsfMRI studies are emerging as important tools to understand the mechanisms and principles of resting state large scale brain activity because they can be accompanied by genetic manipulations and causal interventions aimed to mimic pathologies [18][19][20]. The use of physiologically accessible species can also crucially allow a more precise measure of the underlying axonal connectivity and its directionality [21][22][23], which cannot at present be estimated in humans with Diffusion Tensor Imaging (DTI), as this technique lacks information on fiber directionality, and does not allow to reliably resolve long axonal tracts [24].…”

Adaptation shapes local cortical reactivity: from bifurcation diagram and simulations to human physiological and pathological responses

“…For example, in some vegetative state patients, lesions, compressions or displacements of brainstem activating systems as well as a critical load of damage to ascending fibers in subcortical white matter may enhance potassium currents (Steriade et al, 1993; Edlow et al, 2012), which corresponds to an upward shift in the bifurcation diagram. In other cases, cortical injuries and white matter lesions can engender a state of cortico-cortical disfacilitation by affecting the excitation term (Takahashi et al, 1981; Lemieux et al, 2014; Rocchi et al, 2022). In this case, the resulting loss of lateral and long-range excitatory input would act by producing shifts on the horizontal axis toward the left, to a point where the probability of evoking an Off-period in an awake patient becomes higher.…”